Largely as a result of human failures, drug-resistant Mycobacterium tuberculosis has emerged as a major global public health threat and resistant strains have been identified in most countries. In under-resourced countries, irregular drug supply and poor tuberculosis (TB) management infrastructure have been associated with a vicious cycle of inadequate treatment, the generation of TB drug resistance and transmission of resistant strains. For decades, global and national (TB) control programs have focused their efforts on patients with newly diagnosed TB, as they represent most of the disease burden. However, when compared to new TB cases, patients presenting with TB and a history of previous treatment (re-treatment TB cases) have poor treatment outcomes, increased mortality and higher rates of drug resistance. Importantly, the prevalence of multi-drug resistant TB (MDR-TB), defined as resistant to at least rifampicin (RIF) and isoniazid (INH), is 5-10 fold higher in re-treatment TB cases than in new cases. Efforts to address the problem of drug-resistant TB (DR-TB) in resource-poor settings face several difficulties. The standard re-treatment TB regimen in low-income countries includes five first-line antituberculous drugs. Our hypothesis is that screening for drug resistance to the two most critical drugs to guide prompt initiation of appropriate treatment will accelerate sputum culture conversion and will reduce mortality. The opposing hypothesis is that such screening for partial drug resistance to guide treatment is not associated with improved clinical outcomes. This proof-of-concept study will determine the efficacy and safety of a new strategy to diagnose and treat patients with drug resistant TB attending the Mulago Hospital TB clinic in Kampala, Uganda. The study design will be a phase II, 6-month, open label, randomized clinical trial. Randomization will be done into two strata, defined by HIV status. The intervention arm will evaluate the impact of two simultaneous interventions (targeted rapid drug resistance testing and standardization of second-line drug regimens) on TB treatment outcomes. The control arm will follow the current World Health Organization (WHO) recommendation for re-treatment TB patients. The primary study endpoint will be time to sputum sterilization based on sputa obtained at monthly intervals during the 6-month period following enrollment. Secondary endpoints will include all cause mortality, time to sputum AFB smear conversion, proportion culture negative at each study month, amplification of drug resistance and rate of adverse events. We will also analyze the costs associated with each study arm. This study addresses the control of DR-TB, a present global concern. The results of this study will be immediately available and relevant to a growing population of patients with DR-TB in Uganda and other low income countries. We anticipate the results from this study will provide strong evidence to support a change in the WHO global policy for re-treatment TB in low-income settings. This study will be conducted at a site and by investigators that represent one of few existing research programs on DR-TB in sub-Saharan Africa, a continent at the epicenter of the growing global threat of TB drug resistance.